Outline

Objective: In ParkinsonÂ´s disease, intracerebral transplantation of fetal dopamine cells has been analyzed as a new treatment option. While some patients showed improvements of motor function and reductions of motor fluctuations such as L-DOPA-induced dyskinesia (LID), some patients developed a new type of off-medication dyskinesia now known as graft-induced dyskinesia (GID). The reasons for the development of GID are unclear, but since some of the patients with GID had high preoperative LID-scores, we decided to analyze the predictive value of preoperative LID for the development of GID in the rat Parkinson model.

Methods: All animals first received unilateral 6-OHDA lesions into the MFB in order to induce complete dopamine-denervating lesions. Amphetamine-induced rotation (2,5 mg/kg i.p.) and cylinder test were performed to evaluate the severity of the lesion. Daily L-DOPA injections (6 mg/kg s.c.) were performed for 4 weeks to induce stable dyskinesia. LID was maintained thereafter by injection of L-DOPA twice weekly throughout the experiment. Animals then received transplants of fetal ventral mesencephalon into the striatum. Transplant-induced changes were analyzed in amphetamine-induced rotation at 18 weeks post-grafting, and in the cylinder test at 3 and 15 weeks post-grafting. LID was analyzed at 2, 4, 12, 16 and 24 weeks post-grafting. GID induced by amphetamine (1,5 mg/kg i.p.), was analyzed at 5 and 17 weeks post-grafting. Animals were perfused at 24 weeks post transplantation. Immunohistochemistry was performed for TH-positive grafted cells and fibers. Number of grafted cells was assessed using stereology. Striatal optical fiber density was assessed in the whole or in the caudolateral striatum.

Results: All grafted groups showed significant amelioration of amphetamine-induced rotation and significant improvements in the cylinder test. LID was significantly reduced in animals with severe preoperative LID, and remained low in grafted animals with low preoperative LID. GID was more pronounced in animals with severe preoperative LID and less severe in animals with low preoperative LID values.

Conclusions: Our data indicate, that the severity of preoperative LID predicts the risk for the development of GID in the rat Parkinson model. This suggests, that patients with severe LID should not receive intracerebral dopamine grafts.